Your Digest for Thursday, Nov 16, 2023 05:59 PM


Hypothalamus

Is a bilateral collection of nuelcei divided into three zones surrounding the third ventricle and the mammillary bodies.

Gross anatomy

![HPA Axis anatomy.png](HPA Axis anatomy.png)
locationHypothalamus.png
thalamusLocation.png
hypothalamicNuclei.png

Micro anatomy

PituitaryAnatomyHormones.png
pituitaryHormones.jpg

Hypopituitarism

[!info] ACTH and TSH are the "hardiest" trophic hormones
Organic pituitary disease affects GH AND GONADOROPHINS >> ACTH AND TSH.
ACTH and TSH are the "hardiest" trophic hormones.
The "G" hormones are more sensitive

Causes of hypopituitarism

[!info] Hypothalamic Vs. Pituitary causes
Pituitary lesions won't reduce ADH secretion but hypothalamic lesions will reduce ADH secretion

Hypothalamic diseases Pituitary diseases
Mass lesions – Benign (craniopharyngiomas) and malignant tumors (metastatic from lung, breast, etc) Mass lesions – Pituitary adenomas, other benign tumors, cysts
Radiation – For CNS and nasopharyngeal malignancies Pituitary surgery
Infiltrative lesions – Sarcoidosis, Langerhans cell histiocytosis Pituitary radiation
Infections – Tuberculous meningitis Infiltrative lesions – Hypophysitis, hemochromatosis
Other – Traumatic brain injury, stroke Infection/abscess
Infarction – Sheehan syndrome
Apoplexy
Genetic mutations
Empty sella

![Encodrinology MCQ discussion#Panhypopituitarism](Encodrinology MCQ discussion#Panhypopituitarism)

Growth hormone

Growth Hormone Physiology

[[2021-Basic Sciences#Glucose regulating hormones|IGF]] <<- Action of IGF

[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation]]

Hormone Type Site of secretion Mechanism of action Receptor Sites Effects Transport Pattern of secretion
Peptide Somatotroph cells of Anterior pituitary Mainly acts on the liver to stimulate IGF-1 production, Acts directly and indirectly on epiphyseal bone cell membrane receptor (esp. on hepatocytes). Receptor defects cause Laron dwarfism Pulsatile (10 pulses per day, 90 minutes each -easy to miss in a spot sample)

Stimulation: GHRH, Ghrelin
Inhibition : Somatostatin

Pattern of secretion:
GH secretion peaks in early puberty
Then gradually decreases.

growthHormoneControlRegulation.png
growthHormoneActions.png

GH activation is mediated by many signalling pathways including the JAK2-STAT pathway.

[!TIP] IGF Vs. GH Vs. Insulin
Despite GH having anti-insulin effects, IGF-1 has insulin like activity

Factors increasing GH secretion

Actions of GH

#2020BSQ-NOV/Q10

[!Tip] Mnemonic: GH affects all macromolecules - makes things grow

Other metabolic actions:
Positive nitrogen and phosphorous balance.
Metabolic rate is increased, serum cholesterol is reduced.
Na and K+ retention. (not adrenal gland mediated)
Rise in plasma phosphoros, positive nitrogen balance (but lower serum amino acid levels)
Decrease in blood urea nitrogen.
Apparently, there's an increase in urine ammonia excretions despite a positive nitrogen balance. Source and Source

Causes of GH abnormalities

Reduced secretion

In adults, causes are the same as causes of [[Hormone Physiology#Hypopituitarism|hypopituitarism]].
In children, GH deficiency can be caused by various inherited causes as well. (Acquired causes are same as in adults)

Increased secretion

Commonest cause in adults: somatotroph adenoma

Commonest causes in children: Early childhood GH excess is usually due to GHRH excess. (i.e usually not a tumour). They will present with gigantism (or tall stature)

Causes of Increased GH presenting as gigantism (i.e ↑ GH before epiphyseal fusion)
+ Most commonly due to isolated GH excess
+ Could also be due to
+ McCune-albright syndrome - diagnosed in young adults
+ Carney complex - presents in middle aged people
+ MEN 1 and MEN 4 (4th to 5th decates of life)
+ Neurofibromatosis
+ Famlilial isolated pituitar adenomas - autosomal dominant #autosomalDominant

[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation|Diagnosis and Investigation of GH disorders]]

Acromegaly

Associated features and pathologic basis

As commonest cause is somatotroph adenoma:
acreomegaly is associated with symptoms caused by pressure effect of adenoma:

  1. Headache, bitemporal hemianopia, cranial nerve defects
  2. Decreased secretion of other pituitary hormones -> most commonly gonadotrophins
    1. Menstrual dysfunction, vaginal atrophy, galactrorrhea
  3. Hyperprolactinaemia - either increased [[#Prolactin]] secretion from the somatotroph adenoma or inhbition of dopaminergic inhibition
  4. Effects of GH and IGF-1 Excess:
    1. Soft tissue overgrowth - large tongue, carpal tunnel syndrome + the other classic ones
    2. Joints - Hypertrophic arthorpathy, back pain, kyphosis, hypogonadism induced osteoporosis
    3. Visceral organ enlargement - thyroid, heart, liver, lungs
      1. heart: cardiomyopathy and LVH with diastolic dysfunction and arrhythmias - secondary to hypertension
      2. Hypertension: GH-IGF-I excess -> enhanced sodium- and water retention -> expansion of plasma volume and increased systemic vascular resistance. Source
        3. Hyperinsulinaemia may also stimulate salt and water retention Source
    4. Metabolic - insulin resistance and DM
    5. Sleep apnea
    6. colonic neoplasms

Calcium disorders

[!Info] Hypercalcemia is MUCH more common than hypocalcemia
Usually due to primary hyperparathyroidism; occurs in older females
primary hyperparathyroidism and malignancies = 90% of cases

^da9653

[!WARNING] Hypercalcaemia >>> hypocalcaemia
Hypercalcaemia is much more common than hypocalcaemia

Calcium regulation

Vitamin D

Vitamin D = cholecalciferol.
7-dehydrocholesterol -> + sunlight -> previtamin D3 -> Vitamin D3 --> action liver -> 25-hyroxy cholecalciferol (calcidiol) -> action of kidney -> 1,25 dihydroxy cholecalciferol. (calcitriol)
vitaminDActivation.png
Activated vitamin D (1,25 dihydroxyvitamin D) regulates gene transcription by binding to intracellular receptors.
Mechanism: dihydroxycholecalciferol binds to it's receptor and acts as a transcription regulator which increases calbindin D proteins.
This proteins increases intestinal calcium absorption.
Induction of another protein in the renal tubules increases renal calcium absorption.

^83ab8b

The renal 1-alpha-hydroxylase enzyme which activates vitamin D is regulated!
The main factors are:

#2020BSQ-NOV/Q09
When calcium is high, 1,25-dihydroxycholecalciferol synthesis is reduced and inactive 24,25-dihydroxycholecalciferol is produced instead.

Activated vitamin D levels are elevated in #pregnancy

The main reason for hypocalcemia in CKD is the impaired activation of vitamin D.
Extrarenal synthesis of vitamin D occurs in granulomatous diseases such as sarcoidosis.
regulationOfCalciumLevel.png

Parathyroid hormone

type Site Mechanism Receptor sites Effects Transport Pattern of secretion
peptide Chief cells of parathyroid gland ↑ osteoclast bone resorption, ↑ intestinal absorption, ↑ synthesis of D3, ↑ renal rubular resorption, ↑ phosphate excretion cell membrane

^0f3395

Functions of Parathyroid hormone

Main action is to 'mobilize calcium from bone' and increased renal phosphate excretion.

PTH increases renal phosphate excretion and increases plasma calcium by:

Parathyroid hormone secretion is directly inhibited by high calcium levels.
This happens through binding of calcium to a GPCR on the parathyroid cells called CaR.

[!INFO] Familial hypo and hypercalcemia
Loss of function mutations of CaR cause chronically elevated Calium levels. (Familial hypocalciuric hypercalcemia. (i.e normal to elevated PTH)
Gain of function mutations of CaR cause familiar hypercalciuric hypocalcemia. (?supressed PTH)

Magnesium is needed for the action of PTH. Hypomagnesaemia impairs PTH release and impairs peripheral organ sensitivity to PTH.

PTH level increases with age, possibly due to declining renal function -> reduced activated Vit D level, declining oestrogen levels and / or declining calcium absorption. Source

Calcitonin

#2021BSQ-NOV Q08

Indications for therapeutic used:

Renal handling of calcium

^070bf7

About half of total calcium is protein unbound. The remainder ('complexed' to citrate and phosphate and 'unbound') making up the other half is the 'filtrable' part.
Almost all the filtered calcium is reabsorbed.
RenalCalciumMgPhosphatehandling.png

Region Mechanism Percentage
PCT Passive 60%
TAL 15%
DCT (site of regulation) Active 15%
Collecting duct 0%

PTH and activated vitamin D promote calcium re-absorption in all areas except the PCT. (DCT, TAL, Connecting tubules)
Source

PTH and activated vitamin D promote expression of calcium transport proteins in these regions.
Source ^84acf2

Hypercalcaemia

[[Encodrinology MCQ discussion#Q 10: Hypercalcemia|MCQ discussion]]

Causes are devided into

malignancy and primary hyperparathyroidism = 90% of cases.

![Causes of hypercalcaemia.png](Causes of hypercalcaemia.png)

Causes of Severe hypercalcaemia :

Investigations for hypercalcaemia

Types of Hyperparathyroidism

Primary hyperparathyroidism

Secondary hyperparathyroidism

Physiological compensatory mechanism for hypocalcemia.
Therefore, ↑ PTH levels, but normal calcium level.

Tertiary hyperparathyroidism

After chronic secondary hyperparathyroidism, gland becomes autonomous.
↑Ca2+ and ↑↑ Phosphate

Hypocalcaemia

Not very common

Hypoparathyroidism

In hypoparathyroidism, there is increased bone minieral density. But the bone is not properly formed.
So there are increased fractures

Pseudohypoparathyroidism

Caused by a defect in PTH receptor
Biochemical manifestations are just like hypoparathyroidism (Low Ca2+ and high Phosphate)
BUT having HIGH PTH level
Patients have albright phenotype

Pseudo-pseudo hypoparathyroidism

Patients have albright phenotype BUT
All biochemistry is normal

Phosphate and calcium

[!NOTE] What is the relationship between Calcium and Phosphate?
Calcium phosphate is insoluble and Ca and PO4 can remain in solution so long as the solubility product is not exceeded.
In patients with hyperphosphataemia, there is indeed deposition of calcium phosphate. (familiar tumoural calcinosis)
So it makes sense that as a physiological mechamism, PTH increases calcium level and simultaneously decreases phosphate level. to prevent CaPO4 deposition

To illustrate this further:
"The ensuing hyperphosphatemia may induce potentially symptomatic hypocalcemia due to calcium-phosphate precipitation in the tissues." - Source: Hyperphosphatemia

Phosphate physiology

Prolonged hyperphosphataemia causes hyperparathyroidism and periarticular and vascular calcification.

Hyperphosphataemia

Common in CKD

Hypophosphatemia

Can cause muscle (including diaphgram) weakness. (can cause extubation / weaning failure)
Box 9.23 in K and C #TODO

Regulation of bone formation and resorption - bone metabolism

Two types of bone formation

Osteoclasts arise from macrocyte / monocyte lineage.
Cytokines essential for osteoclast function:

Bone development includes

An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological cellular changes in the most common bone diseases, including osteoporosis

Factors influencing bone turnover

Bone deposition and resorption is influenced by both systemic and local factors.

Systemic Local
+ PTH & calcitriol Prostaglandin
GH / IGF-1 Transforming growth factor (TGF)
Glucocorticoids Bone morphogenic proteins (BMP)
thyroid hormones Cytokines
sex hormones (Levels of local regulators are influenced by mechanical stress, local inflammation etc.)

More complicated than you might think:

Decrease bone turnover Increase bone turnover
Parathyroid hormones - Intermittent administration -> Stimulates bone formation PTH - Continous presense --> bone resorption
Calcitriol (1,25 dihydroxycholecalciferol) If Ca and PO4 are low, high levels of Calcitriol can stimulate resorption
Estrogens - decrease bone turn over glucocorticoids (glucocorticoid induced osteoporosis)
Calcitonin - physiologically redundant, pharmacologic doses -> onyl a transient effect of reducing bone resorption Thyroid hormones - BOTH deposition and resorption. (bone loss can occur in hyperthyroidism)
TGF beta adn BMP

Fibroblast growth factors - involved in skeletal development. Receptor mutations cause achondroplasia. [[Hormone Physiology#Growth hormone|See Laron Dwarfism]]

Thyroid hormone

Overview of physiology

Synthesis of thyroid hormone

Synthesis occurs in follicular cells
Inorganic iodine -> Oxidation -> incorporation into thyroglobulin -> converted to MIT and DIT
MIT and DIT are converted to T3 and T4. More T4 is produced than T3. --> Bound to TBG (and albumin) --> transported.
SynthesisOfThyroxine.png

StepsInThyroidHormoneSynthesis.png

[!INFO] only unbound (FREE) thyroid hormones can act on tissues.
only unbound (FREE) thyroid hormones can act on tissues. However, the protein bound fraction is very important for buffering and storage of thyroid hormone to prevent rapid fluctuations.

T3 binds to nuclear recetpor --> Exerts effects

T4 = prohormone (mnemonic "four" rhymes with "pro")
T3 = active metabolite; synthesized from T4 in periphery.
![TSH regulation.png](TSH regulation.png)

Functions of thyroid hormone

thyroidHormoneFunctions.png
Thyroid hormone binds to it's nuclear receptors.
There are two isoforms - TR alpha and beta, expressed in different tissues.
Receptor-T3 complexes alter gene expression.
Overall effects of T3:
#2022BSQ Q23

System effect
CVS Increase cardiac ouput
RS Maintains respiratory drive
GI increases motility
Blood Incr. 23-DPG - increased oxygen unloading
Muscles Increase speed of muscle contraction
Carbs Increase gluconeogen, glycolysis, sugar absorption
lipid Lipolysis + increased cholesterol turnover
Sympathetic NS Increases expression of beta adrenergic receptors and in heart decreases alpha receptors

Investigation of thyroid function

TSH levels

There is a negative log-linear relationship between serum free T4 and TSH concentrations [1]. This means that very small changes in serum free T4 concentrations induce very large reciprocal changes in serum TSH concentrations. As a result, thyroid function is best assessed by measuring serum TSH, assuming steady-state conditions and the absence of pituitary or hypothalamic disease

Low TSH usually means hyperthyroidism except in

High TSH + High fT4 = TSHOma (rare) or Thyroid hormone resistance.
For this situation, administration of TRH (TRH test) will stimulate further TSH releast only in thyroid hormone resistance (TSHOma is autonomic and not controlled by TRH)

Thyroid peroxidase antibodies

Thyroid peroxidase – TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine. Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of TPO antibodies.
Also found in 80% of Grave's disease patients.

Hyperthyroidism

![Evaluation of hyperthyroidism.png](Evaluation of hyperthyroidism.png)

3 Common causes

  1. Graves
  2. TMNG
  3. Solitary nodule / adenoma
    See [[Evaluation of hyperthyroidism.png]]

Graves' disease

#2021BSQ-NOV Q32

[!INFO] Is an autoimmume, T cell infiltrative disease.

gravesDisease.png

[!INFO] Definition of Graves ophthalmopathy:
Ophthalmopathy is characterized by inflammation of the extraocular muscles and orbital fat and connective tissue, which results in proptosis (exophthalmos), impairment of eye muscle function, and periorbital edema.

(In a child with thyrotoxicosis) the presence of eye findings such as exophthalmos or ocular muscle dysfunction essentially always points to Graves disease. "Stare" and lid lag are common in children with any form of hyperthyroidism and occur due to increased sympathetic tone.

Volume of retro-orbital tissue is increased by 1) T cell infiltration, 2) Inflammatory oedema, 3) Increased extracellular matrix deposition, 4) increased adipocytes.
Graves dermopathy and ophthalmopathy may also be due to TRAb antibody reactivity with eye and skin tissue which may also express TSH receptor like protein. - UpToDate.

^4c27cc

[!INFO] Eye signs
Lid retraction: can be of the upper or lower eye lid. Definitions are varied and confusing.
Lid lag: Failure of the upper eye lid follow the globe as the gaze is moved donwards.
Source
As above, lid retraction is more suggestive of Grave's ophthalmopathy.

Others causes of hyperthyroidism: ![Causes of hyperthyroidism.png](Causes of hyperthyroidism.png)

Management of hyperthyroidism

Symptomatic management: Propronolol for beta blockade.
Antithyroid drugs : thionamides: Carbimazole / methimazole and PTU
Methimazole is active metabolite of carbimazole; Equivalent dose of carbimazole is 40% higher.

[!TIP] C --> M: Alphabetical order

[!TIP] Mnemonic
PTU has a T

  1. It's good in T1 of pregnancy
  2. and thyroid STORM
  3. hepaTic Failure,
  4. vasculiTis

#2022BSQ Q16
#2021BSQ-NOV Q20

Both inhibit thyroid peroxidase which inhibits iodination of tyrosine residues on thyroglobulin.

#2020BSQ-NOV/Q20

Carbimazole / methimazole Propylthiouracil
General advantages of PTU: Achieves euthyroid state more quickly, Once daily dosing, less likely to cause failure of radioiodine therapy Usually second choice except for T1, T storm
Less severe side effects. Usually first line choice Usually second line, except T1 of pregnancy, <- preferred in T1
and thyroid storm
Blocks 5'-monodeiodinase, which converts peripheral T4 to T3 conversion
Less frequent teratogenic effects
Pruritus, rash, arthritis, urticaria, abnormal taste Same
Agranulocytosis (0.1% incidence) Same
Less risk of hepatic injury (?can cause cholestatis) Fulminant hepatic failure
ANCA positive vasculitis

Euthyroid status is expected in 4 - 6 weeks.

[!TIP] Pharmacokinetics of carbimazole / methimazole are generally better than PTU.
Carb/methimazole has longer half life.
High intrathyroidal concentrations, outlasting the plasma half life.
More inhibition of iodine organification.

Rash: Usually can be treated with antihistamine, stoppage of thionamide not required. Cross reactivity to different thionamide seen in 50%.

Agranulocytosis:
Thionamides have a high risk of agranulocytosis compared to other drugs that cause it.
Agranulocytosis occurs within 2-3 months of start of treatment.
If it occurs, treatment with thionamides is contraindicated.

Hypothyroidism

causesOfHypothyroidism.png

Hashimoto thyroiditis (chronic autoimmune thyroiditis)

Types of Thyroiditis

Thyroiditis typically causes a painful goiter.

[!TIP] Mnemonic
De quervain - painful
Hasimotos's - chronic
hashimotosMnemonic.png
Grand Seikos are japanese watches -> chronic ;)

Hashimoto's De quervain Post partum Drug induced radiation Infectious Silent
chronic autoimmune - months to years Post viral thyroiditis - days rare, around 6 months post partum, resolves by 12 months PP Lithium, interferons radio-iodine therapy rare, bacterial infection
Rubbery gland Painful, warm thyroid
Transient hyper, then hypothyroidism Hyper and then hypothyroidism
risk factors: type 1 DM and previous episodes
De quervain (subacute thyroiditis)

#2021GM-JUL/Q23

[!INFO] Biochemical changes in subacute thyroiditis
patternOfBiochemicalChangesDeQuervainSubacuteThyroiditis.png
Adapted from UpToDate

Riedels thyroiditis :

Source

fibrous thyroiditis (Reidel's thyroiditis) -> fibrosis of the thyroid gland; woody, hard gland on palpation. Thyroid parenchyma becomes slowly replaced with dense fibroid tissue.
Presentation: Dyspnoea, Dysphagia, hoarseness due to involvement of extrathyroidal structure by the fibrosis.

Sick euthyroid syndrome

Image 1 Image 2
![hormone levels sick euthyroid syndrome.png](hormone levels sick euthyroid syndrome.png) ![hormones in sick euthyroid.png](hormones in sick euthyroid.png)

Deranged Physiology
T3 : Low (peripheral conversion of T4 to T3 is reduced, therefore T4 may be increased)
TSH : Not elevated (i.e low or normal)
rT3 : elevated (inactive form of T3; Is a T3 antagonist)

Occurs in ill / critically ill patients.
It may be that TSH is physiologically lowered to prevent a catabolic state.
In general, thyroid functions should not be done in critically ill patients because results can be misleading.

Replacement of thyroxine is not helpful in sick euthyroid symdrome. Management is to treat the underlying disease process.

Levothyroxine

Levothyroxine (aka L thyroxine) is synthetic T4.

Prolactin

Prolactin is secreted by lactotroph cells in the anterior pituitary.
Level of secretion of prolantin due to a given stimulus proportional to background hyperplasia of lactotrophs which is driven by oestrogen.
Prolactin secretion by lactotrophs is under tonic inhibition of dopamine (which acts on D2 receptors of the lactotrophs) secreted by the tuberoinfundibular pathway, originating in the arcuate nucleus of the hypothalamus.

Hyperprolactinaemia causes amenorrhoea.
StatPearls prolactin

Causes of hyperprolactinaemia

  1. Lactotroph adenoma - usually very high prolactin levels.

  2. Loss of dopaminergic inhibition

Oestrogen tends to increase prolactin levels.

Management of hyperprolactinaemia

Dopamine agonist = cabergoline and bromocriptine.
Cabergoline has less side effects.

Microadenoma -> Dopamine agonist
Macroadenoma -> dopamine agonist -> surgery

Insulin

Production and Secretion of insulin

secretionOfInsulin.png
Increased blood glucose -> uptake of glucose into beta cells by GLUT-2. --> Converted to glucose-6-phosphate by islet specific glucokinase --> takes part in cellular respiration --> increased ATP --> closes ATP dependent pottasium channels --> depolarization --> influx of calcium --> secretion of golgi vessicles.
High serum amino acid also stimulates glucose secretion.

Dysfunction of islet specific glucokinase can cause one type of MODY.

Mechanism of action of insulin

Insulin binds to the insulin receptor -> it has insulin dependent tyrosine kinase activity.

  1. Liver ->
    1. inhibits glycogenolysis <- inhibition of Glycogen phosphorylase enzyme
    2. and gluconeogenesis. <- indirect effect (reduced flow of gluconeogenic precursors to the liver etc.)
    3. increases glygogen synthesis <- stimulates glycogen synthase
  2. Skeletal muscle + adipose tissue->
    1. Increases glucose uptake <-( Translocation of GLUT-4 to the membrane -> increased glucose uptake)
      1. Under euglycaemic conditions, most of the insulin mediated glucose uptake occurs in muscle.
    2. Increases glycolysis (i.e respiration) <- Stimulation of hexokinase and 6-phosphofructokinase
  3. Adipose tissue
    1. inhibits lipolysis <- Inhibition hormone sensitive lipase
    2. Increased triglyceride synthesis <- indirectly by increasing availabiligy of glycerol 3 phosphage due to stimulation of glucose entry and glycolysis
    3. Insulin stimulates adpiose tissue lipoprotein lipase and inhibits muscle lipoprotein lipase (LPL)

[!INFO] Insulin helps to coordinate between different types of fuel used by the body.
InsulinAction.jpg
Coordination of glucose and lipid metabolism by insulin

  1. in the fed stage, insulin secretion promotes glucose utilization AND storage of triglyceride in fat cells.
  2. In the fasting state, deficiency of insulin conserves glucose and mobilizes stored triglyceride.

Overall effect of insulin on lipid metabolism = Diversion of TGL from muscle to adipose tissue for storage.
The overall effect of increased triglyceride storage and decreased lipolysis is decreased flux of free fatty acids to the liver. This has indirect but potent action of reducing hepatic gluconeogenesis and hepatic glucose output.

Hypoinsulinaemia:

 Under hypoinsulinemic conditions, such as prolonged fasting or uncontrolled diabetes mellitus, fat mobilization is greatly accelerated, resulting in an oversupply of free fatty acids to the liver. In this situation, the liver synthesizes ketone bodies from the abundant supply of acetyl CoA, a by-product of incomplete beta-oxidation of long-chain fatty acids. => [[General medicine 5#DKA pathophysiology|Diabetic ketoacidosis]]

Other hormones regulating blood glucose level

#2021BSQ-NOV Q07

Glucose transporters

[!TIP] Mnemonic
GLUT-2 and GLUT-4 : even numbered ones are involved in insulin mediated glucose regulation.
1 and 3 are basal, non insulin dependent transporters.

Transporter Site
SGLT-1 small intestine and renal tubules
SGLT-2 renal tubules
GLUT 1,3 basal glucose uptake 'everywhere', GLUT-3 very abundant in brain
GLUT 2 beta cell glucose sensor
GLUT 4 insulin mediated glucose uptake in Sk and cardiac muscle, adipocytes
GLUT 5 Fructose transporter

Oestrogen

There are three main types of estrogen: Source

Cushing's syndrome and Cushing's disease

Features of Cushing's syndrome

  1. Osteoporosis
  2. Hypertension
  3. Facial plethora, proximal myopathy, striae, easy bruising
  4. Hypokalemia can occur [[#^6a91b2]].

[!INFO] Epidemiology of Cushing's syndrome and disease
Women are x3 to x8 time more likely than men to have Cushing's disease.
and x4 times more likely to have Cushing's syndrome due to adrenal tumour.

Males had a three times greater incidence of the ectopic ACTH syndrome 30 years ago, but the increasing incidence of lung cancer in cigarette-smoking females has narrowed that margin

Commonest cause is iatrogenic;
All glucocorticoids suppress ACTH -> ACTH, and serum cortisol will be low in iatrogenic cushing's syndrome.

The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal, and physiologic hypercortisolism has been excluded

Sequence of evaluation:

evaluationSuspectedHypercortisolismCushing.png
If a patients has feature of Chushing's syndrome

  1. It has to be proved that the patient has elevated cortisol
  2. The cause of elevated cortisol must be determined.

Initial testing to confirm elevated cortisol:

  1. bedtime salivary cortisol

    1. There is a pre-bed time cortisol level nadir in normal physiology.
    2. This is preserved in physiologic hypercortisolism but absent in Cushing's syndrome.
  2. 24 hour urinary free cortisol - Measures the total daily cortisol production without being affected by the cyclical variations in it's production.

  3. Low dose DST

    1. The low-dose DSTs are standard screening tests to differentiate patients with Cushing syndrome of any cause from patients who do not have Cushing syndrome.
    2. A positive low dose DST will show impaired suppression of cortisol secretion.
    3. The high-dose DSTs are not used to make the diagnosis of Cushing syndrome. (High dose DST is used to identify the source of ACTH if it is abnormally high (i.e Cushing's disease Vs. ectopic ACTH)
    4. There are two forms of low dose DST
      1. Overnight 1mg dexamethasone suppresion test
      2. two day 2 mg DST
    5. Both will show impaired suppression of cortisol if the patient has Cushing's syndrome.

For bedtime salivary cortisol and UFC, two abnormal tests are required.

Pseudo-Cushing's syndrome

If cortisol is found to be elevated with the above preliminary tests, next step is to exclude physiologic hypercortisolism.
AKA - pseudo Cushing syndrome.

Clinically, these patients usually do not have skin or muscle manifestations of Cushing Syndrome.
Causes of pseudo-cushing syndrome (i.e causes of elevated cortisol)

  1. #Pregnancy
  2. Severe obesity / PCOS
  3. Severe major depression
  4. Poorly controlled DM
  5. OSA

Because of various nuances, the above tests must be unequivocally elevated in order to diagnose Cushing's syndrome. Mild elevations are unlikely to indicate Cushing's syndrome.

Determining the cause of hypercortisolism

Once hypercortisolism has been identified and physiologic hypercortisolism as been excluded, the cause of hypercortisolism must be determined.

First step is determining if the cortisol hypersecretion is
ACTH dependent or ACTH independent.
This is done by measuring ACTH levels.

ACTH levels

Because of cyclical variations, testing at two different times is recommended.

ACTH < 5pg/ML = ACTH independent hypercortisolism

ACTH > 20pg/mL = ACTH dependent hypercortisolism.

ACTH dependent Hypercortisolism

  1. The vast majority have pituitary corticotroph adenoma -(CUSHING'S DISEASE)
  2. Other causes are ectopic ACTH and ectopic CRH.

Determining the cause of ACTH dependent hypercortisolism

  1. CRH stimulation test - differentiates Cushing's disease from all other causes of hypercortisolism
    1. Corticotroph pituitary tumours respond to CRH (despite being tumours) -> AC
  2. High dose dexamethason suppression test
    1. Corticotroph tumours are not resistant retrain sensitivity to negative FB by glucocorticoids
    2. Ectopic ACTH producing tumours have absolutely no inhibition from glucocorticoids. (with the exception of some pulmonary neuroendocrine tumours)
    3. Therefore, 8mg of Dexamethasone oral at 11PM will cause reduction in morning Serum cortisol.
  3. Desmopressin stimulation test
    1. Used clinically when CRH is not available
    2. ADH stimulates ACTH release.
    3. Desmopressin is used to mimic this effect. (ADH and desmopressing have a similar action to CRH)
      1. In ACTH secreting adenoma (Cushing's disease) this response is preserved but in ectopic ACTH secreting lesions this response is absent.

Imaging

A mass > 6mm in size in the sella turcica supports a diagnosis of Cushing's disease.
10% of healthy people have masses <6mm in size.

Invasive testing

Sampling the ACTH level from the petrosal sinus can be used if the diagnosis is uncertain.
duralVenousSinuses.png

[!INFO] Hypokalemia in Cushing's syndrome

^6a91b2

Adrenaline synthesis

[!TIP] Mnemonic
Dopamine -> Norad -> adrenaline -> ?waste products

adrenalineSynthesisMonoamines.jpg

See also: figure 2 here: Source


Toxicology: unknown substance

#2023SBR-NOV/Q09

Context: 45 year old male presenting with ingestion of a poison causing cholinergic symptoms and hypertension with tachycardia.

Antidotes

Atropine:
Fuller's earth: A type of clay used as an adsorbent, filter or bleaching agent. Used in 'kitty litter' to remove the smell of cat urine.
Medically, used for treatment of paraquat ingestion, because [[Toxicology#Paraquat poisoning|Paraquat]] is intended to break down in soil. Source


See Note in MD Work on "Overview of infections and treatment"

==HIGHLIGHTS== = working hypothesis ;) Could change

Good Links

Antibiotic protocols for ICU

Antibiogram

Overview of Infections and treatment - Obsidian work

H. pylori eradication

[!INFO] Regime: PPI with amoxicillin + clarithromycin | metronidazole
Read below to see why these drugs are used

Overview of beta lactam antibiotics

betaLactamOverview.png

Penicillins

Overview of the development of penicillins

Source
Source

==for some reason, penicillin won't work well against gram -ve bacteria==

Resistance to beta lactams

Major concerns are with Streptococcus pneumoniae and Pseudomonas aeruginosa.

Amoxicillin

A beta lactam
Beta lactamase susceptible ! - Flucloxacillin is penicillinase resistant.
Amino group added to penicillin for some extra gram negative coverage.
Also has improved coverage of Listeria monocytogenes and Enterococcus sp

Effective against many gram positives:
-Strep pneumoniae
-pneumococci
-enterococci
Also some gram -ve

When to consider Amoxicillin

Oral amoxicillin (once or twice daily) has easier dosing schedule than oral penicillin - 6 to 12 hourly (Penicillin V).
Amoxicillin is now usually given as Co-amoxiclav . Clavulanic acid "restores" activity of amoxicllin against resistanct bacteria.

Extended spectrum penicillins ticarcillin and piperacillin-taz are active against pseudomonas

Flucloxacillin

penicillinase resistant - DOC in serious MSSA infections.
Considered narrow spectrum.
Effective against Staph and Streptococcus pyogenes

==? Coamoxiclav and flucloxacillin are interchangeable==

Flucloxacillin and Co-Am can cause obstructive jaundice and hepatitis

Carbapenems

Source

. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as “slow substrates” or inhibitors of β-lactamases

Among beta lactams, carbapenems possess the broadest spectrum of activity and greatest potency against Gram-positive and Gram-negative bacteria

Carbapenems were discovered as a result of the search for beta lactamase inhibitors around 1970. (As beta lactamases were threatening the usefulness of penicillin at this time)

Thienamycin was a beta lactamase inhibitors that proved to be the parent molecule for all the Carbapenems.

Remarkably, thienamycin demonstrated potent broad-spectrum antibacterial and β-lactamase inhibitory activity including inhibitory microbiological activity against

  1. Gram-negative bacteria, including isolates of Pseudomonas aeruginosa, as well as
  2. anaerobes, like Bacteroides fragilis, and
  3. Gram-positive bacteria, such as methicillin- or oxacillin-susceptible Staphylococcus aureus and streptococci
    Imipenem (synthesized around 1985) was the first practically usable derivative of thienamycin.
    (Imipenem is broken down by a renal brush border enzyme)

Generally speaking, carbapenems enter Gram-negative bacteria through outer membrane proteins (OMPs), also known as porins.

Meropenem, biapenem, ertapenem, and doripenem are slightly more effective against Gram-negative organisms

(i) ertapenem has a more limited spectrum, because it is not as active as imipenem or meropenem against P. aeruginosa (164); (ii) meropenem is not as potent as imipenem or doripenem against Acinetobacter baumannii (164);

Antipseudomonal carbapenems – imipenem, meropenem and doripenem – have excellent activity against most strains of many bacterial species and are regarded as safe and generally well-tolerated. Of note, these carbapenems are resistant to ESBLs, and so are of value in treating infections caused by ESBL-producing strains of Enterobacteriaceae
Source

unique application of meropenem is that when combined with clavulanic acid, it is potent at killing MDR Mycobacterium tuberculosis, a bacterium that typically is not susceptible to β-lactams due to a chromosomally expressed β-lactamase.

**Many class A β-lactamases are susceptible to inhibition by clavulanic acid (26). In contrast, all class C and most class D β-lactamases are not inhibited by clavulanic acid. However, class A and C and certain class D enzymes are inhibited by carbapenems. **

Several carbapenems were designed to target MRSA while maintaining activity against most Gram-negatives. The anti-MRSA activity is related to the high affinity of these compounds for PBP2a of MRSA. However, research on these compounds have been mostly abandoned. (Except for two)

Why clarithromycin? Why is it interchangeable with metronidazole

Macrolides - Erythromycin has a very similar (not identical) spectrum to penicillin.
Mechanism: Macrolides inhibit the 50s ribosomal subunit and inhibit protein synthesis.
They are mainly bacteriostatic.

BUT both oral and IV erythromycin have significant side effects - so clarithromycin is used (having less SE but similar specturm. )

[!TIP] ==Penicillin ≈ clarithromycin==

So amoxicllin and clarithromycin are combined probably because they have different modes of action (although they have similar spectrums)

Clarithorymycin is good for

Azithromycin

is a macrolide.

Gentamicin

[!INFO] Gentamicin
Aminoglycoside antibiotic for gram -ve coverage.
Consider when penicillins are contraindicated and in mixed infections. Source

RE management of febrile neuropenia:

Give empirical antibiotics as per local policy and sensitivities:
• Commonly used antibiotics should include activity against enteric
Gram-negative bacteria and Pseudomonas, e.g. ceftazidime or
piperacillin–tazobactam with gentamicin; or meropenem monotherapy

Enterobacter, pseudomonas and Acinetobacter require high dose gentamicin / amikacin treatment.

Mechanism
Inhibition of protein synthesis by intefefering with ribosomal function.
Good activity against gram negatives - E. coli, klebsiella, psuedomonas,

Synegistic with penicillins used in endocarditis against Enterococcus and streptococcus viridans.
Amikacin - similar spectrum and has activity against gentamicin resistant organisms; only use if gentamicin won't work.

#2022SBR Q12
Gentamicin is supposed to cause ?non-oliguric renal failure!

Piperacillin tazobactam

No need for combination with metronidazole because it has good anaerobic coverage

Ciprofloxacin

Fluoroquinolone: Inhibits DNA synthesis.
Active against Streptococci, Staph epidermidis and some MRSA and also most gram -ve organisms including pseudomonas.

Works for acinetobacter! (Surprise!!)

Clindamycin

A lincosamide - not a macrolide.
Inhibits protein formation by inhibiting the 50s ribosome.
Strongly assosiacted with C. difficile infection. Therefore, use should be minimized.
Doesn't penetrate the BBB -> can't use in meningitis.
Peak concentration reached within 60 minutes of oral administration.

Spectrum: Useful against gram +ve cocci --> severe streptococcal or staphylococcal cellulitis.
Has activity against PVL producing S. aureus.

A very high proportion of GI microbes are anaerobic.

Treatment of MRSA infection

Vancomycin or Teicoplanin.

Teicoplanin is a glycopeptide antibiotic that is almost identical to vancomycin with regard to its antibacterial spectrum of activity. - ScienceDirect

Teicoplanin is preferred in renal impairment.

Antibiotics with anaerobic cover

#2022BSQ-MAY Q41

Source
Source

Microorganisms are

  1. Facultative (aerobic or anaerobic)
  2. Microaerophillic - require lower-than-atmospheric oxygen concengrations.
  3. Obligate anaerobic.
    1. Oxygen can be actually toxic to anaerobes and they are also classified based on tolerance to oxygen.

Obligate anaerobes are found as commensals in

  1. mucous membranes - specially the oral cavity.
  2. lower GI tract
  3. Vagina

Obligate anaerobes replicate at sites with low oxidation-reduction potential (eg, necrotic, devascularized tissue).

Anaerobic infections frequently occurs due to growth of a mixed population of bacteria with anerobes and facultative anaerobes.

Common sites of anaerobic infections:

  1. Upper airways - dental infection, deep neck space, chronic rhinosinusitis
  2. Pleuropulmonary infections
  3. Intra abdominal infections
  4. Female genital tract infections
  5. Deep soft tissue infections

anaerobicPathogenClassification.png.png

Source

Common gram negative anaerobic pathogens:

  1. Bacteroides (most common) - Gram negative bacilli - Intra abdominal infections
  2. Fusobacterium - Gram negative bacilli - Abscesses and wound infections, pulmonary infections.
  3. Porphyromonas - Aspiration pneumonia and periodontitis.
  4. Prevotella - intra-abdominal, dental, gygaecological and soft tissue infections.

Common gram positive anaerobic infections:

  1. Actinomyces (not a fungus lol) : head, neck, abdnominal, bone, pelvic and aspiration pneumonia.
  2. 😓Clostridia😓 - Endospore forming Gram +ve bacilli - intra-abdominal (clostridial necrotizing enterocolitis), soft tissue infection, gas gangrene (C perfringens), botulism, tetanus, clostridium difficile induced colitis and diarrhoea.[[2023-SEMPaper#Clostridium difficile]]
  3. Peptostreptococus - seems to be an important one.
  4. Cutibacterium (formerly propionibacterium) - foreign body infections (CSF fluid shunt, prosthetic joint, cardiac device)

Most of the pathogens we know are facultative anaerobic.
Obligate anaerobes include the following:

  1. Bacteroides fragilis + other bacteroides species
  2. Spore formers - Clostridium
  3. Actinomyces

Anaerobic infections are usually suppurative.

Clues to suspect anaerobic infection:

  1. polymicrobial results on gram stain and culture
  2. Sterile aerobic cultures despite bacteria on gram stain
  3. Gas within infected tissues
  4. Foul odour
  5. Necrotic tissues
  6. Site of infection near mucosa where anaerobes usually live

Source
Antibiotics which are always active against anaerobes:

Aminoglycosides are not effective for anaerobes.

Vancomycin is active against Gram +ve anaerobes - (i.e clostridia)
Clindamycin - variable activity against anearobes. 40% of bacteroides and some clostridia are resistant.

Beta lactamases

Beta lactamases inactivate antibiotics with a beta-lactam ring.
Carbapenems are a sub-class of beta lactam antibiotics. Enzymes which inactivate carbapenems are called carbapenemases.

There are several types of microbial enzymes having beta lactamse activity; they have been c lassified by Ambler class.

  1. Ambler class A: Extended spectrum beta lactamases(ESBLs): Found in klebsiella, E coli and Enterobacterales.
    1. They inactivate extended spectrum penicillins (piperacillin Tazobactam), most cephalosporins and monobactams (monobactams = aztreonam)
    2. ESBL producing bacteria are sensitive to carbapenems except for klebsiella

Klebsiella pneumoniae carbapenemases (KPCs) are similar to ESBLs except that they also hydrolyze carbapenems!.

  1. Ambler class B: called Metallo-beta-lactamases: They can inactivate all beta lactams, including carbapenems except for aztreonam. Present in stenotrophomonas, Klebsiella, Pseudomonas and Acinetobacter.
  2. There are also Amblcer Class C and D.

Beta lactamase inhibitors:

  1. Clavulanate, sulbactam, tazobactam - They block penicillinases, But NOT carbapanemases or Ambler Class C beta lactamases. Sulbactam itself has antibacterial effects against Acinetobacter baumanii, Neisseria gonorrhoea and Bacteroides fragillis.
  2. There are no beta lactamse inhibitors against Ambler Class B beta lactamases.

Cephalosporins

[!INFO] Development of cephalosporins
In 1945, after penicillin had been introduced into medicine, an antibiotic-producing species of Cephalosporium was isolated from a sewage outfall in Sardinia. Four years later in Oxford, this organism was found to produce several antibiotics, one of which was a penicillin with a new side-chain, penicillin N. During a chemical study in 1953, this penicillin was shown to be contaminated with a second substance, cephalosporin C, which contained a beta-lactam ring but was resistant to hydrolysis by a penicillinase (beta-lactamase). At that time, penicillinase-producing Staphylococci were causing a serious problem in hospitals. The isolation of the nucleus of cephalosporin C (7-ACA) enabled pharmaceutical manufacturers to produce many thousands of cephalosporins, some of which have been effective in the treatment of serious infections by a number of Gram-positive and Gram-negative bacteria.

Mechanism of action: They are beta lactam antibiotics; Mechanism of action: inhibition of bacterial cell wall synthesis

https://www.medigraphic.com/pdfs/lamicro/mi-2007/mi07-3_4g.pdf

gen 1: Cefazolin, Cephalexin

First generation : most gram +ve cocci and some gram negative bacteria
(including penicillinase-producing Staphylococcus aureus)
"minimal coverage of gram -ves" but a few Gram -ves are susceptible.
(gram -ve's including E coli, klebsiella, proteus).
Clinically used for uncomplicated skin and soft tissue infections.

Gen 2:

Cefuroxime
Haemophilus infeluenza, Moraxella, bacteroides

cefuroxime has increased coverage against H. influenzae.

Second-generation cephalosporins have less activity against gram-positive cocci than first-generation cephalosporins but have increased activity against gram-negative bacilli

They are often prescribed to treat respiratory infections such as bronchiolitis or pneumonia.

In addition to the gram-negative bacteria covered by first-generation cephalosporins, second-generation cephalosporins also have coverage against H. influenzae, Enterobacter aerogenes, Neisseria species, and Serratia marcescens

Gen 3:

Less coverage against gram +ves but increased coverage Enterobacteriaceai, Neisseria and H influenzae.
Ceftazidime:

Gen 4:

similar to gen 3 but better activity against gram -ves with antimicrobial resistance. (like beta lactamases)
Cefepime:

Gen 5:

have coverage against MRSA and penicillin resistant pneumococci.

Specific pathogens

Haemophillus

https://www.msdmanuals.com/professional/infectious-diseases/gram-negative-bacilli/haemophilus-infections
Fastidious gram -ve cocco-bacillus.

bacteremia, meningitis, pneumonia, sinusitis, otitis media, cellulitis, and epiglottitis

the most common is H. influenzae, which has 6 distinct encapsulated serotypes (a through f) and numerous nonencapsulated, nontypeable strains. Before the use of H. influenzae type b (Hib) conjugate vaccine, most cases of serious, invasive disease were caused by type b.

Non typable strains can cause upto half of H influenze infections in adults.

Pseudomonas

#2021BSQ-NOV Q18

[!WARNING] Most common HAI
It's a frequent cause of nosocomial infections; the most common pathogen isolated from patients hospitalized for > 1 week.

Going by the stuff that's already in this note:
#2020BSQ-NOV/Q19

Pseudomonas is a

#TODO
C. difficile